There is a wide array of microorganisms that are pathogenic to man, and other organisms. Pathogenic bacteria, viruses, rickettsia, and fungi may cause disease in their host organism whether plant, animal, or man.
Fungal diseases of man and animals, often referred to as mycoses, may be classified into two broad categories. Deep tissue, or systemic mycoses involves the wide dissemination of pathogenic fungi growing in internal organs, and tissue, and superficial mycoses, which generally represent different types of pathogenic fungi than those that infect the skin, hair, nails and mucosa.
Deep tissue mycoses including aspergillosis, actinomycosis, blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, nocardiosis, paracoccidioidomycosis, entomophthoromycosis and occasionally candida, may infect the lungs, brain, bones, spinal fluid, liver, heart, kidneys, and other internal organs, as well as the skin. Depending on severity, deep tissue mycoses may cause illness that ranges from asymptomatic to life threatening.
Superficial mycoses, also called dermatophytosis, describe disorders such as ringworm, athlete's foot, favus and candida, which infect the skin, hair, nails and mucosal linings. There are perhaps three dozen or so known species of pathogenic fungi, and yeasts responsible for causing these diseases.
The National Health Survey of 1971-1974 projected from its sampling that about one out of every twelve people in the United States had some form of dermatophytosis, with men being four times more likely than women to contract infections.
Surveys of other nations reveal a much higher incidence of superficial mycotic diseases, among the poor, and underdeveloped countries of Africa, Asia, South America, and those areas of the world having tropical climates.
Tinea is another term used to describe ringworm. It is usually followed by another term which describes the particular location of the infection. Hence, athletes foot is often referred to as "tinea pedis". Scalp ringworm is also known as "tinea capitis"; body ringworm as "tinea corporis", jock itch as "tinea cruris" etc. Though not considered to be life threatening, as some deep tissues mycoses can be, superficial mycoses assuredly take a fair toll of man and animals in misery, inconvenience, and expense.
Though not classified as a serious illness by the medical profession, this does not necessarily reflect the view point of those sufferers of superficial fungal infections. On a personal level, an athlete whose performance on the playing field is diminished because of painful cuts on the feet due to an athlete's foot infection, may consider it to be a serious illness.
A young woman who develops bald patches on her scalp due to ringworm may feel that she has a serious illness. It is also likely that she may feel the same about a ringworm infection of the fingernails, where the nails assume a horrible, unsightly appearance as a result of thickening, brittleness and discoloration typical of the disease. Add to this a year and a half of systemic treatment to see results, and she may feel that she indeed has a very serious illness.
Do people who are unemployed, low income, or without medical coverage consider an illness, that in addition to causing discomfort, can cost them several hundred dollars a year in treatments, and still not be cured? Do ranchers think of ringworm as a serious disease, when the feed lots, who are paying high prices for livestock, refuse their herd because of ringworm? I think the answer is a resounding "yes!."
Antibiotic drugs such as penicillin, tetracycline, and sulfa ect., though often effective in the treatment of bacterial infections, are useless against infections caused by viruses, rickettsia, and fungi. Fungal disorders, for example require treatment with a separate group of antimicrobial drugs, known as antifungals, or antimycotics.
Antimycotic drugs (FIGS. 14-16) were first introduced in the 1950's with nystatin (1954), amphotericin B (1958), and griseofulyin (1959). These drugs were originally administered systemically. Tolnaftate (FIG. 17) was introduced in 1965 as the first effective topical antifungal treatment. Since the 1970's, a number of "azole" derivative antifungals such as clotimazole (FIG. 20), miconazole (FIG. 21), econazole (FIG. 22), ketoconazole, and others have made their appearance as antimycotics for both systemic, and topical administration. The more current trend has been toward the developement of a "triazole" (FIG. 23) class of antifungals, including such derivatives as fluconazole (FIG. 24), terconazole (FIG. 25), and itraconazole ect.
Prior art treatments for superficial mycoses, in addition to being expensive, require repeated application before improvement can be seen in the patient. Currently available over the counter treatments, containing clotrimazole, miconazole, tolnaftate, or undecylenic acid, recommend up to sixty applications of the product in order to provide full benefit. More treatments are often required.
Regardless of economic impact, even wealthy individuals, with the best health care available suffer with all the others when it comes to the discomfort, and bother of repeated application of medication that is slow acting, and often ineffective at producing cure or relief of symptoms.
Even prescription topical antifungals, administered by a dermatologist, may require as many as two hundred applications over a period of three months to cure some cases of athlete's foot alone. Nail infections may require eighteen months of multiple, daily treatment to provide cure. In addition to being very expensive and time consuming, applying the medicine repeatedly each day is bothersome. Coupled with the discomfort of the fungal disorder, the expense, and inconvenience associated with the treatment adds further to the misery of the condition.
The current cost of treating ringworm and other superficial mycoses excludes the economically disadvantaged, who suffer most from the condition, from receiving treatment. Poor sanitation, a lower standard of general health, along with the fact that it is rarely treated, adds to the greater prevalence of ringworm, and other superficial mycoses among lower income individuals. To a low income family in the United States, an extra five dollars a week expense to buy the cheaper topical over the counter fungal treatments can cause real hardship on the household budget. For the disadvantaged of many developing countries, five dollars a week looks more like a good wage for a healthy working man supporting a family, than what one can afford to pay to treat a skin condition that takes weeks to cure, if it can be cured at all. For these reasons, superficial mycoses among the poor usually go untreated, being prohibitive because of the cost of treatment.
In this respect, the current array of prior art antifungal treatments have failed to significantly heal superficial mycoses throughout the world, being inaccessible to most of the world because of cost. In addition to the misfortune of not having viable treatment for tens of millions of sufferers of fungal infection, no markets are created, and no products sold, to the advantage of no one. Prior art antifungal treatments keep the price of treatment high, the market volume small, and undiverse, and only bring marginal relief to a relative few of the many suffers.
The bad economics of currently available topical antifungals prohibits their use in the livestock industry, as well. The cost of the medicine, coupled with the labor required for repeated application to livestock, forbids the creation of a significant market for these medicines within the industry. As stated earlier, livestock infected with ringworm are refused by feed lots. The rancher holding them back, in turn, raises his prices to cover this liability; effecting all processors and consumers of meat products.
Ringworm, being highly contagious, can spread through a herd within a few short weeks, not allowing enough time for treatment and recovery in the weeks prior to going to market, even if they are treated. With the current way of topical antifungals, treating food animals for ringworm is an absurd notion. The cost involved in applying a medicine, perhaps fifty times, to a single head of livestock could never be justified. For this reason, treatment is withheld, to the disadvantage of both the rancher and the animal, which in addition to suffering discomfort, spreads the disease to other animals, perpetuating the cycle further. In addition to money lost, no viable solution is offered by pharmaceutical manufacturers which would otherwise enjoy a new, very large potential market.
Whether or not one feels the economic impact of superficial mycoses, all suffers experience the inconvenience of having to make repeated application of currently available prior art topicals. The necessity of making repeated applications is an indication of weak drug action, and that is another great flaw of prior art antifungal treatments.
Systemic antifungal drugs are also used to treat superficial mycoses, in addition to the deep tissue diseases. Drugs like amphotericin B, clotrimazole, enconazole, griseofluvin, ketoconazole, miconazole, and nystatin, are administered internally, usually orally, or by injection. Like the topical antifungals described earlier, most of the systemics treatments require multiple doses in order to be effective. Systemic treatments are the most costly of all, requiring the supervision of a physician. They are most dangerous to the patient, with undesirable side effects that can further endanger the health of the patient. The risk of damage to internal organs, and adverse reactions to other medications, are factors that must be carefully weighed by physicians administering systemic antifungals. With this, other less severe, yet unpleasant side effects, include nausea, vomiting, headache, dizziness, fever, diarrhea, and many other adverse effects that contribute to the misery and ill health of the patient.
Amphotericin B (FIG. 14), given by injection in the treatment of systemic fungal infection, carries with it the risk of liver and kidney damage, and can also result in blood disorders. It interacts negatively with many cardiac medications, and diuretics, as well as other antibiotics.
Griseofulyin (FIG. 16), usually taken orally, for fungal infections of the skin, hair, and nails, has a risk of liver damage. Reduced bone marrow function, with lowered white cell levels is another possible adverse effect of treatment. Drug interactions with anticoagulants, and barbiturates reduce effectiveness, and the risk to pregnancy often forbids treatment.
Ketoconazole, taken orally for systemic fungal infections, also carries the risk of liver damage as a result of treatment. The effectiveness of ketoconazole is diminished by interaction with various antacids, and other gastric medications. Ketoconazole increases the potency of other drugs, and is reduced in potency by some antibiotics.
Miconazole (FIG. 21), taken by injection for fungal infection of the lungs, brain, kidney, and lymph nodes, can alter blood chemistry resulting in anemia. Miconazole also interacts negatively with medications for diabetes, epilepsy and anticoagulants. The effectiveness of amphotericin B is reduced by miconazole.
Nystatin (FIG. 15), taken orally for candida disorders, is of little use in the treatment of systemic fungal infections. Though having far fewer adverse side effects than the other antifungal drugs, it is ineffective against most fungal infections except candida, and aspergillus, making it of limited usage.
Treatment with these systemic antifungals often produces many other very unpleasant side effects, in addition to the adverse effects upon blood composition, internal organs and other medications being taken by the patient. Taken internally, amphotericin B, griseofulyin, ketoconazole, miconazole and nystatin, may cause nausea, vomiting, diarrhea, dizziness, headache, fever and other disorders during the coarse of treatment. These symptoms, though unpleasant enough for the patient, can also lead to more serious complications, further advancing the ill health of the patient. Beside these known adverse effects, others yet unknown, will be discovered with further research. The full effect of internal treatment with antibiotics on the body is a very complex matter, and warranting much caution.
Topical treatment of superficial mycoses is much safer than internal treatments. The prior art, however, has failed to produce topical antifungal medications effective enough to deal with more serious infections. This necessitates the use of systemic treatments, which are more dangerous, costly, time consuming, and associated with many other unpleasant illnesses to treat even superficial mycoses.
The adverse effects of prior art systemic antifungal treatments is a more serious complication of treatment for deep tissue mycoses than superficial mycoses. Patients suffering from deep tissue disorders, such as cryptococcosis, histoplasmosis, blastomycosis, coccidioidomycosis, paracoccidioidomycoses, and others, are generally in a much poorer state of health than patients being treated for dermatophytosis. For this reason, the adverse effects of systemic treatment have greater impact on the overall health of patients being treated for deep tissue mycoses. This is of particular significance in the treatment of immunocomprimised patients.
Deep tissue mycoses find their greatest opportunity in immunocomprimised patients. These include cancer, organ transplant patients, and others on immunosuppressant medication, and particularly with patients suffering from immune disorders such as acquired immune deficiency syndrome, otherwise known as AIDS. These patients, who are very ill indeed, are highly susceptible to infection from these diseases, as their natural defenses against the pathogenic microbes is greatly reduced.
The adverse effects of treatment with currently available prior art systemic antifungals, are devastating to immunocomprimised patients, to the point of being themselves life threatening to the patient- To those patients in greatest need of treatment for deep tissue mycoses, the medication is most dangerous to administer.
With the steady rise in treatment with immunosuppressant drugs, and the much more dramatic rise in the number of cancer, and AIDS cases reported, and anticipated for the future, the demand for safe, effective, and low cost treatments for both deep tissue, and superficial mycoses, is more urgent than ever. The prior art has largely failed to meet this criteria as a result of high cost, low ineffectiveness, and the high toxicity of their antifungal medications.
The focus of the prior art upon the development of azole derivatives, is perhaps largely responsible for keeping the cost high, and the effectiveness of antifungal treatments so low. The newer generation triazole (FIG. 23) derivatives, including fluconazole (FIG. 24), terconazole (FIG. 25), itraconazole, and others, cost many millions of dollars to develop, and apparently are not that much more effective than the prior generation imidiazole (FIG. 19) derivatives, and certainly are doing nothing to make treatment more affordable, or convenient. Beside this, they have much narrower application than the imidiazoles, and are considered auxiliary, and not mainline treatments.
It seems doubtful at this point, that either of the azole groups will produce derivatives of significantly greater effectiveness in the treatment of fungal disorders, than what is currently available with prior art treatments.